Systems and methods for treating autism spectrum disorders (asd) and related dysfunctions

ABSTRACT

Systems and methods for treating autism spectrum disorders (ASD) and related dysfunctions are disclosed. A method in accordance with a particular embodiment includes determining that a patient suffers from an autistic disorder and, based at least in part on the determination, selecting a cortical signal delivery site. The method can further include implanting an electrode within the patient&#39;s skull and external to a cortical surface of the patient&#39;s brain, and treating the autistic disorder by applying electrical signals to the implanted electrode in conjunction administering an adjunctive therapy to the patient.

CROSS-REFERENCE TO RELATED APPLICATION

The present application claims priority to U.S. Provisional ApplicationNo. 61/057,144 filed May 29, 2008 and incorporated herein by reference.

TECHNICAL FIELD

Aspects of the present disclosure are directed generally toward systemsand methods for treating autism spectrum disorders (ASD) and relateddysfunctions.

BACKGROUND

The Autism Spectrum Disorders (ASD) range from a mild form calledAsperger syndrome to more severe forms—autistic disorder, Rett syndromeand childhood disintegrative disorder. ASD is characterized by deficitsin social interaction and verbal and nonverbal communication.Stereotyped, repetitive behaviors like hand flapping or head banging arecommon in more severe cases. It has been claimed that deficits inimitation and empathy suggest that there is an underlying deficiency inthe “theory of mind,” which is the ability to understand that othershave beliefs, desires and intentions that are different from one's own.

ASD can be detected as early as 12 to 18 months but often is notdiagnosed until the age of 3 years. Autism currently affects 0.34% ofchildren between the ages of 3 and 10 years old. ASD is a developmentaldisorder and in many cases, early detection is important so thatintervention can begin at a young age. Existing treatments includebehavioral therapies that focus on developing communication and socialinteraction skills. Medications are available to treat behavioralproblems, e.g., selective serotonin reuptake inhibitors (SSRIs) foranxiety and depression, and antipsychotic medications for severebehavioral problems. Anticonvulsants are used to treat seizures, andstimulants are used to treat inattention and hyperactivity. Thepathology of ASD is poorly understood and it does not appear that any ofthese medications treat the underlying causes. Accordingly, there is aneed for improved ASD treatments and associated treatment systems.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a block diagram illustrating a representative method inaccordance with an embodiment of the disclosure.

FIG. 1B is a schematic diagram of a system in accordance with anembodiment of the disclosure. FIG. 2 illustrates pathways to thesomatosensory, visual and auditory association areas.

FIG. 3 illustrates unimodal sensory inputs converging on multimodalassociation areas in the prefrontal, parietotemporal, and limbiccortecies.

FIG. 4 illustrates the flow of sensory information at dorsal and ventralpathways.

FIG. 5 illustrates the prefrontal and parietal association areas andinterconnections between these areas.

FIGS. 6A-6B illustrate the flow of information in the motor controlsystem.

FIG. 7A is a schematic illustration of selected neurons.

FIG. 7B is a graph illustrating the firing of an “action potential”associated with normal neural activity.

FIG. 7C is a graph illustrating firing and “action potential” associatedwith neural activity affected by a method in accordance with anembodiment of the disclosure.

FIGS. 8A and 8B are schematic illustrations of an implanting procedurein accordance with an embodiment of the disclosure.

FIG. 9A is an isometric illustration of an implantable signal deliverydevice configured in accordance with an embodiment of the disclosure.

FIG. 9B is a cross-sectional view schematically illustrating animplantable signal delivery device configured in accordance with anembodiment of the disclosure.

FIG. 10 illustrates a system for providing therapy to a patient inaccordance with an embodiment of the disclosure.

FIG. 11 is a top plan view of a portion of the brain with a signaldelivery device positioned in accordance with a particular embodiment ofthe disclosure.

FIG. 12A is a top, partially hidden isometric view of a signal deliverydevice configured in accordance with another embodiment of thedisclosure.

FIG. 12B is an internal block diagram of a signal delivery deviceconfigured in accordance with yet another embodiment of the disclosure.

FIG. 13 illustrates a computer-generated image of a human head and facedisplaying each of six facial emotions during the articulation of theword “please.”

FIG. 14 illustrates an expanded factorial design for four auditoryemotion categories and four visual emotion categories.

FIG. 15 illustrates the probability of correct responses from ahypothetical control group of normal adolescent subjects as a functionof visual and auditory stimuli corresponding to four different emotionalcategories.

FIGS. 16A-16F illustrate representative active brain regions for normalsubjects and autistic subjects responding to emotions presented by aface.

FIGS. 17A-17B further illustrate active brain regions for normal andautistic subjects when responding to emotions presented by a face.

FIGS. 18A-18F illustrate representative target neural populations forstimulation in accordance with particular embodiments.

FIGS. 19A-19B illustrate representative hypoactive areas in autisticpatients.

FIG. 20 illustrates the proportion of correct responses byrepresentative normal subjects when presented with unimodal and bimodalauditory and visual stimuli corresponding to four different emotionalcategories in accordance with a particular embodiment.

FIG. 21A illustrates representative brain areas active during speechprocessing in a normal subject, and FIG. 21B compares active brain areasfor normal and autistic subjects.

FIG. 22 is a schematic block diagram illustrating representative patientprocessing of audible and visible speech in a face-to-face dialog for anormal subject.

FIG. 23 illustrates an expanded factorial design for three auditoryspeech categories and three visible speech categories that can be usedfor patient assessment and/or treatment in accordance with a particularembodiment.

DETAILED DESCRIPTION

Aspects of the present disclosure are directed generally to systems andmethods for treating autism spectrum disorders (ASD) and relateddysfunctions. In general, representative methods can include identifyingsuitable target sites, applying electromagnetic signals and/or othertreatment modalities at the target sites, and, in at least someinstances, administering an adjunctive therapy in conjunction with theapplied signals. Several details describing structures and processesthat are well known and often associated with such systems and methodsare not set forth in the following description for purposes of brevity.Moreover, although the following disclosure sets forth severalrepresentative embodiments of systems and methods for treating ASD,several other embodiments can have different configurations and/ordifferent components than those described in this section. Accordingly,such embodiments may include additional elements and/or may eliminateone or more of the elements described below with reference to FIGS.1A-23.

Overview

FIG. 1A is a flow diagram illustrating a representative process 180 inaccordance with an embodiment of the disclosure. The process 180 caninclude determining that a patient suffers from an autistic disorder(e.g., ASD), as identified in process portion 182. This determinationcan be made, for example, on the basis of patient responses to testingand/or specific symptoms exhibited by the patient. Process portion 184can include selecting a cortical signal delivery site, based (at leastin part) on the determination that the patient suffers from an autisticdisorder. Selecting the cortical signal delivery site can include anevaluation and analysis process. For example, as shown in processportion 186, the process can include evaluating the patient's responsesto one or more stimuli, e.g., auditory and visual stimuli correspondingto human emotional states. The patient evaluation can include, inaddition to assessing the patient's performance on tests, reviewing thepatient's history for details of specific symptoms or sets of symptoms,and identifying the most severe and/or debilitating symptoms.

Process portion 188 includes, based at least in part on the individualpatient's responses to one or more selected stimuli, determining whetherthe patient has a neurological defect associated with the responsebehavior. For example, the defect can be associated with a patient'sresponse to auditory stimuli, visual stimuli, or both. Process portion189 includes determining whether to engage the patient in treatment(e.g., a new treatment regimen or a revised treatment regimen). Inprocess portion 190, the process includes, based at least in part on thedetermination of the patient's neurological defect, selecting a corticalsignal delivery site that is different depending on the characteristicsof the defect. For example, the cortical signal delivery site can bedifferent depending upon whether the defect is associated with thepatient's response to and/or processing of auditory stimuli, visualstimuli, or both. Process portion 190 can include acquiring functionalimaging data during appropriate behavioral tests, for example, responsesto the stimuli corresponding to human emotional states. In otherembodiments, electrophysiological data can be collected with scalpelectrodes and analyzed, instead of or in addition to performingfunctional imaging. For example, a localized desynchronization of EEGactivity can be used to identify hypoactive neural populations. In otherembodiments, a power decrease in the EEG spectrum or changes incoherence can be indicative of hypoactivity or other neurologicaldefects.

In process portion 192, a signal delivery device is provided to addressthe neurological defect. For example, the signal delivery device caninclude an electrode implanted within the patient's skull and externalto the cortical surface of the patient's brain. In process portion 194,the autistic disorder is treated by applying electromagnetic signals tothe signal delivery site. In particular embodiments, the signals areapplied in conjunction with administering an adjunctive therapy to thepatient, for example, a behavioral therapy (process portion 196). Theprocess 180 can then return to process portion 186 for a re-evaluationof the patient. The practitioner can continue the patient treatment ifwarranted by the evaluation performed in process portions 186 and 189,and if not, the process 180 can end. For example, if the patient hasresponded favorably to the treatment regimen, but the patient's responsehas stabilized, the treatment (e.g., the stimulation, possibly augmentedby behavioral therapy) can be concluded.

As used herein, the term “stimulation” is used generally to includeelectromagnetic signals applied to a target neural population.Accordingly, the signals can include electrical signals applied to thepatient's brain via a cortical implant, (e.g., cortical stimulation, orCS), a deep brain implant (e.g., deep brain stimulation, or DBS), and/ora transcranial technique (e.g., transcranial direct current stimulationor tDCS). Magnetic signals can be applied transcranially usingrepetitive transcranial magnetic stimulation or rTMS. Though generallyreferred to as “stimulation,” the signals may have direct or indirectfacilitatory effects, inhibitory effects, and/or plasticity-enhancingeffects, as will be described further later.

FIG. 1B is a schematic illustration of a system 100 that can be used toevaluate and/or treat a patient P in accordance with several embodimentsof the disclosure. The system 100 can include an evaluation/adjunctivetherapy system 135 and a signal delivery system 130. Aspects of bothsystems 130, 135 can be controlled at least in part by a processor 101.The processor 101 can be a single shared processor, or separateprocessors can be provided for each of the signal delivery system 130and the evaluation/adjunctive therapy system 135. Theevaluation/adjunctive therapy system 135 can further include inputdevices 102 and one or more output devices 103 that are operated by apractitioner, therapist, and/or the patient to provide data regardingthe patient's dysfunctions before, during, and/or after treatment.Information received during one or more evaluation processes can be usedby the practitioner and, in at least some instances, automatically bythe system 100 to initiate, control, and/or update the therapy providedto the patient P. The therapy provided to the patient P is provided by asignal delivery device 120 (e.g., an implanted or non-implantedelectromagnetic stimulator) that is under the control of a controller142. The overall system 100 can be operated in an open-loop format toprovide initial and/or updated treatment regimens, or the patient(generally with assistance from a practitioner) can provide responsesvia the input devices 102 that are then automatically used to update thesignals directed from the controller 142 to the signal delivery device120, in a closed-loop format.

Representative Brain Functions

Brain imaging studies have implicated a number of cortical andsubcortical regions that may play a role in ASD. Structural imaging andpostmortem studies have reported increased total brain volume inautistic patients. The cerebellum has been extensively investigated inautistic patients, but early findings have not always been replicated.Other studies have reported anatomic anomalies in the corpus callosum,amygdala, hippocampus and cingulate cortex, but again, it has not alwaysbeen possible to replicate these findings. Significant decreases in graymatter within the temporal lobes have been reported, especially in andaround the superior temporal gyrus. This last finding is consistent withfunctional imaging studies discussed below.

Functional imaging studies (as compared with structural imaging studies)have also identified a number of regions that may potentially contributeto autism. Positron emission tomography (PET) and functional magneticresonance imaging (fMRI) studies reveal decreased levels of activity inmuch of the prefrontal region—e.g., Brodmann areas 9, 10, 11, 12, 44,45, and 46. Metabolic reductions have also been observed in thecingulate cortex and amygdala, which presumably relates to the flataffect and inappropriate emotional responses exhibited by autisticpatients. The temporal lobes exhibit a highly significant hypometabolismin PET and SPECT imaging. Any one or combination of these cortical areasare candidates for stimulation (e.g., electromagnetic stimulation) inthe treatment of autism. In one embodiment of this disclosure,electromagnetic signals are applied to the cortex to increase theactivity in any and/or all of these regions, because functional imagingstudies repeatedly report hypoactivity in ASD patients, as compared tonormal subjects. However, these cortical regions encompass much of theprefrontal and temporal lobes, and it is not practical to target such alarge cortical region with electromagnetic stimulation. Accordingly,certain embodiments of the present disclosure are directed toidentifying target area(s) for treating autism with greater specificity,so as to improve the efficiency and/or efficacy of the treatment.

The symptomology of autism and the involved cortical regions describedabove suggest that the so-called executive functions have beencompromised in autistic patients. These functions include interpretingsensory information, associating perceptions with previous experience,focusing attention, planning actions, and other cognitive functionsresponsible for organizing appropriate motor responses to incomingsensory inputs. Many of these executive functions are also criticalcomponents of the social brain network, which may explain the socialimpairments seen in even mild cases of autism or Asperger syndrome.Accordingly, aspects of the present disclosure include identifying thetarget areas for receiving electrical and/or other forms of stimulation,based at least in part on the architecture of executive functioning inthe human brain, which is briefly summarized below.

The brain can be viewed as a structure responsible for organizing andimplementing appropriate motor responses to incoming sensory stimuli.Visual, auditory and somatosensory inputs enter the cortex at primaryprocessing centers in the occipital, temporal and parietal lobes,respectively. FIGS. 2-6 are schematic representations of the brain,illustrating selected neural pathways, based on information described byEric Kandel et al. in “Principals of Neuroscience,” 4th Ed. (2000).FIGS. 2-6 are provided to illustrate the general principals associatedwith these pathways—for purposes of illustration, clarity and brevity,particular details of these pathways known to those of ordinary skill inthe relevant art are not shown in FIGS. 2-6.

FIG. 2 illustrates representative brain structures, Brodmann areas, andpathways to the somatosensory, visual and auditory association areas. Asshown in FIG. 2, hierarchical connections between cortical areasprogress from the primary sensory cortex to the unimodal associationcortex to the multimodal association cortex. At each stage,progressively more abstract information is extracted from the sensorystimulus and is projected to the next stage, as is discussed furtherbelow.

Each of the primary sensory processing areas identified above isunimodal—that is, these areas primarily receive and process neuralactivity associated with one sensory modality. Each of these primarysensory regions processes specific aspects of the sensory input, andthen passes it along to secondary sensory regions (unimodal associationcortices) that process more complex aspects of the input. Thesesecondary sensory regions then project to multimodal regions in theprefrontal, parietotemporal, and limbic cortices where the differentsensory modalities are combined to create an integrated sensation orrepresentation of the stimulus. FIG. 3 illustrates unimodal sensoryinputs converging on multimodal association areas in the prefrontal,parietotemporal, and limbic cortices where internal representations ofthe sensory stimulus are assembled.

Along the foregoing pathway, the flow of sensory information is dividedbetween dorsal and ventral pathways. As shown in FIG. 4, the dorsalpathway processes sensory information (e.g., depth and motion) relatingto where objects are located. The ventral pathway processes sensoryinformation (e.g., color, shape and form) relating to what the objectsare. As shown in FIG. 5, the multimodal association areas project to andare interconnected with two “central processors”: the anteriorassociation cortex (e.g., the dorsolateral prefrontal cortex—DLPFC, orsuperior frontal sulcus) and the parietal association cortex (orintra-parietal sulcus) that are also heavily interconnected. Anintegrated representation of the constantly changing world is generatedin the parietal area, while the prefrontal area constructs arepresentation of our body moving in and manipulating this world. It hasbeen suggested that the conscious sense of a coherent self emerges fromthe operation of these two association cortices. This suggestion issupported by evidence indicating that lesions in either region result inselective and restrictive loss of self-awareness for certain types ofstimuli, while maintaining awareness for others. As noted above, theparietal association cortex provides an integrated perception of theconstantly changing world around us while the anterior associationcortex puts our self-image in that world so that we can manipulate it.It is in the interactions between these two cortical regions thatappropriate motor responses are selected for incoming stimuli.

The amygdala and cingulate cortex provide emotions and memories gainedfrom previous experience to guide the selection of appropriate motorresponses. As shown in FIGS. 6A and 6B, the selected response is definedin very general terms initially in the prefrontal cortex but becomesmore specific as the flow of neural activity spreads into the motorcontrol system. The prefrontal cortex selects specific motor responsesand generates motor plans, which are projected to the premotor cortex(as shown in FIG. 6A). The premotor cortex in turn generates the motorprogram or specific sequence of motor actions (FIG. 6B). Finally,neurons in the primary motor cortex activate movements to implement themotor response.

The foregoing network is complex and not always well understood.Accordingly, it is not always readily apparent where the lesion creatingthe ASD occurs. It is also not clear if lesions creating similar ASDs indifferent patients are located at the same or different anatomicalsites. It may not be clear whether the anomalous activities recorded infunctional imaging are indicative of the etiological “source”, or ofsecondary effects at “downstream” sites. In addition, once a suitabletarget site has been identified, the proper stimulation parameters mustbe selected to reduce symptoms and/or facilitate recovery from thisdebilitating disorder. Embodiments of the representative methods,described in further detail below, are directed at dealing with theforegoing uncertainties.

Imaging studies of ASD patients reveal anomalous activity levels(generally hypoactivity) in many of the cortical regions involved inexecutive functions. As noted above, symptoms can also vary widelybetween patients. Some patients are hypersensitive to certain sounds,while other patients are hypersensitive to visual stimuli. Some patientshave better verbal skills than non-verbal skills, while other patientshave better non-verbal skills. This inter-patient variability stronglysuggests that the lesion(s) can be in any of these cortical areas, andthat the lesion(s) can be in different locations in different patients.As implied by the name, ASD is a spectrum of disorders with a wide rangeof symptoms that reflect variability in the affected corticalcomponents.

It could be argued that the primary “lesion” or affected cortical regionis the ideal target for stimulation, and that an effective therapeuticstimulation at this site will cascade through downstream sites tonormalize activity levels there as well. However, it may be difficult todifferentiate between the “primary” lesion and other cortical sitessecondarily affected by input from the primary lesion. At lower levelsin the sensory/motor flow of neural activity, there is a predominantdirectionality so that primary sites can be identified as the “upstream”sites. Thus, for example, if hypoactivity is found in both the secondaryauditory cortex and the parietotemporal multimodal association area, itmay be inferred that the primary lesion is in the secondary auditorycortex. However, at the higher levels, cortical areas becomeincreasingly interconnected and less hierarchical, making it moredifficult to identify the “primary” lesion site. Accordingly, certainembodiments of the disclosed method include obtaining a detailedcharacterization of each patient's symptoms, along with an imaginganalysis of the patient's affected cortical regions, so as to identifythe “primary” site. Specific target sites can be selected, in part, byconsidering which symptoms most adversely affect the patient, and whichcomponent(s) of the executive neural circuitry are most likely involved.In general, once a “primary” site has been identified, stimulation canbe directed to the primary site. If it is later determined (e.g., via afollow-up evaluation) that the deficit at the primary site has beenaddressed, and that a deficit now exists (or still exists) at asecondary site, then the stimulation can be directed to the secondarysite during an additional or further treatment regimen.

Representative Stimulation Methodologies

FIG. 7A is a schematic representation of several neurons N1-N3 and FIG.7B is a graph illustrating an “action potential” related to neuralactivity in a normal neuron. Neural activity is governed by electricalimpulses generated in neurons. For example, neuron N1 can sendexcitatory inputs to neuron N2 (e.g., at times t₁, t₃ and t₄ in FIG.7B), and neuron N3 can send inhibitory inputs to neuron N2 (e.g., attime t₂ in FIG. 7B). The neurons receive/send excitatory and inhibitoryinputs from/to a population of other neurons. The excitatory andinhibitory inputs can produce “action potentials” in the neurons, whichare electrical pulses that travel through neurons by changing the fluxof sodium (Na) and potassium (K) ions across the cell membrane. Anaction potential occurs when the resting membrane potential of theneuron surpasses a threshold level. When this threshold level isreached, an “all-or-nothing” action potential is generated. For example,as shown in FIG. 7B, the excitatory input at time t5 causes neuron N2 to“fire” an action potential because the input exceeds the threshold levelfor generating the action potential. The action potentials propagatedown the length of the axon (the long process of the neuron that makesup nerves or neuronal tracts) to cause the release of neurotransmittersfrom that neuron that will further influence adjacent neurons.

FIG. 7C is a graph illustrating the application of a subthresholdpotential to the neurons N1-N3 initially shown in FIG. 7A. At times t₁and t₂, the depolarization waves generated in response to the intrinsicexcitatory/inhibitory inputs from other neurons do not summate in amanner that “bridges-the-gap” from a neural resting potential at −X mV(e.g., approximately −70 mV) to a threshold firing potential at −T mV(e.g., approximately −50 mV). At time t₃, extrinsic electricalstimulation is applied to the brain, in this case at an intensity orlevel that is expected to augment or increase the magnitude ofdescending depolarization waves generated by the dendrites, yet below anintensity or level that by itself will be sufficient to summate in amanner that induces action potentials and triggers the neural functioncorresponding to these neurons. Extrinsic stimulation signals applied inthis manner may generally be referred to as subthreshold signals. Attime t₄, the neurons receive another excitatory input. In associationwith a set of appropriately applied extrinsic stimulation signals, evena small additional intrinsic input may result in an increased likelihoodthat a summation of the descending depolarization waves generated by thedendrites will be sufficient to exceed the difference between the neuralresting potential and the threshold firing potential to induce actionpotentials in these neurons. Thus, in this situation, the subthresholdextrinsic signals facilitate the generation of action potentials inresponse to intrinsically occurring neural signaling processes. It is tobe understood that depending upon signal parameters, the extrinsicsignals may exert an opposite (disfacilitatory, inhibitory, ordisruptive) effect upon neurons or neural signaling processes, and henceparticular signal parameters may be selected in accordance with alikelihood of achieving a desired or intended therapeutic effect oroutcome at any given time.

The actual signal(s) applied by one or more extrinsic signal deliverydevices positioned in, upon, or above the brain to achieve a therapeuticor intended effect will vary according to the individual patient, thetype of therapy, the type of electrodes (or other signal deliverydevice), and/or other factors. In general, the pulse form(s) of theelectromagnetic signals (e.g., the frequency, pulse width, waveform,current level, and/or voltage) directed toward achieving an intendedtherapeutic effect may be selected or estimated relative to a testsignal level or intensity at which a neural function is triggered oractivated, or a change in a physiologic parameter (e.g., cerebral bloodflow) is detected. Additionally or alternatively, the pulse form(s) ofthe first and/or second electromagnetic signals may be selected,adjusted, modulated, limited, or constrained at one or more timesrelative to parameters corresponding to one or more previously (e.g.,most-recently) applied signals, or a maximum allowable or intended peakor average stimulation signal intensity.

In one embodiment of this disclosure, stimulation is applied tofacilitate plasticity and reorganization of the affected cortex. In thisembodiment, cortical stimulation can be coupled with behavioralcognitive therapies designed to ameliorate the selected symptoms. Inparticular embodiments, signal delivery parameters may be generallysimilar to those expected (based on studies performed by the assignee ofthe present application) to be beneficial for treating otherdysfunctions, including but not limited to stoke. For example, in aparticular embodiment, cathodal electrical signals are applied to atarget neural population at a frequency of from about 50 Hz to about 150Hz (e.g., about 100 Hz), a pulse width of from about 50 microseconds toabout 250 microseconds (e.g., about 100 microseconds), and an amplitude(current or voltage) of from about 25% to about 50% (e.g., about 40%) ofthe activation threshold level for neurons at the target neuralpopulation. Depending on the patient's needs, behavioral therapies caninclude social interactions and/or communication exercises designed toimprove these skills. Further details of representative therapies arediscussed later.

In another embodiment, cortical stimulation can be applied to change theactivity levels in areas found to exhibit anomalous activity levels inthe patient (e.g., to alter the excitability of target neuralpopulations). Typically, ASD patients have regions of hypoactivitycompared to normal subjects, and the stimulation can accordingly be usedto increase this neural activity. This embodiment does not necessarilycombine behavioral therapies with the cortical stimulation (unlike thepreceding embodiment) because this treatment is focused more on changingneural activity levels rather than promoting cortical reorganization. Ina particular embodiment, assuming a hypoactive target neural population,anodal electrical signals are applied at a frequency of from about 75 Hzto about 150 Hz (e.g., about 100 Hz), a pulse width of from about 50microseconds (e.g., about 100 microseconds) and an amplitude (current orvoltage) of from about 25% to about 60% (e.g., about 50%) of theactivation threshold level for neurons at the target neural population.If the target neural population is hyperactive, the practitioner canapply cathodal electrical signals to inhibit the target neuralpopulation, for example, at a frequency of from about 75 Hz to about 150Hz (e.g., about 100 Hz), a pulse width of from about 50 microseconds toabout 250 microseconds (e.g., about 100 microseconds), and an amplitude(current or voltage) of from about 50% to about 75% (e.g., about 60%) ofthe activation threshold level for neurons at the target neuralpopulation. If rTMS techniques (rather than direct cortical stimulationtechniques) are used to affect neural activity levels, the practitionercan select rTMS frequencies of 5-10 Hz and above to treat a hypoactiveneural population, or less than 5 Hz to treat a hyperactive neuralpopulation.

Representative Stimulation Systems

As discussed above, direct cortical stimulation can be used to treatpatients for ASD in many cases. As was also discussed earlier, ASD inmany cases emerges in the first few years of life, leaving the patientwith life-long impairments in social and communication skills.Accordingly, it may be desirable to apply stimulation to the patientbefore the critical period of developing these skills has passed.However, it is generally unlikely that infants will be implanted withcortical stimulation electrodes because the infant's head grows sorapidly that it may be difficult to maintain proper electrodepositioning over the course of a treatment regimen. Accordingly, otherdelivery modalities (e.g., rTMS) may be used for younger patients,and/or in situations in which an implanted electrode is not as suitablefor the patient. Implanted electrodes can be used for teenagers, youngadults, and/or other patients more suited to the use of such electrodes.

In a representative example, the applied electromagnetic signalsdescribed above are delivered by an implanted signal delivery device,shown schematically in FIGS. 8A-8B. Referring first to FIG. 8A, a skullsection 105 is removed from a patient P adjacent to one or more targetneural populations (a single target neural population 104 is shown inFIG. 8A for purposes of illustration). The skull section 105 can beremoved by boring a hole in the skull 106 in a manner known in therelevant art, or a much smaller hole can be formed in the skull 106using drilling techniques that are also known in the art. The hole canbe 0.2-4.0 cm in diameter in a particular embodiment, but can have otherdimensions depending upon factors that include the size (and/or number)of the target neural population(s), and/or the size of the implanteddevice.

Referring to FIG. 8B, an implantable signal delivery device 120 havingfirst and second electrodes or contacts 121 can then be implanted in thepatient P. The contacts 121 can be positioned at or close to the targetneural population for bipolar stimulation (as shown in FIG. 8B), or forother types of multipolar stimulation. In other embodiments, one or moreelectrodes (e.g., return electrodes) can be positioned remote from thetarget neural population for unipolar stimulation. Suitable techniquesassociated with the implantation procedure are known to practitionersskilled in the relevant art. After the signal deliver device 120 hasbeen implanted in the patient P, a pulse system generates electricalpulses that are transmitted to the target neural population 104 by thefirst and second electrodes 121.

FIGS. 9A-12B illustrate signal delivery devices configured in accordancewith a variety of embodiments for providing electromagnetic signals topatients suffering from ASD and/or other dysfunctions. Accordingly,these devices are representative of devices for performing the therapiesdescribed above. The illustrated devices include cranial implants thatsupply electrical current to the brain, as it is expected that suchdevices will provide direct treatment with relatively low powerrequirements. However, in other embodiments, other electromagneticsignals (e.g., magnetic fields) may be provided by other devices (e.g.,transcranial magnetic stimulation devices).

FIG. 9A is an isometric view of a system 130 configured in accordancewith an embodiment of the disclosure for stimulating a region of thecortex proximate to the pial surface. The signal delivery system 130 caninclude an implantable signal delivery device 120 that in turn includesa support member 122, an integrated pulse system 140 (shownschematically) carried by the support member 122, and first and secondelectrodes 121 (identified individually by reference numbers 121 a and121 b). The first and second electrodes 121 are electrically coupled tothe pulse system 140. The support member 122 can be configured to beimplanted into the skull or another intracranial region of a patient. Inone embodiment, for example, the support member 122 includes a housing123 and an attachment element 124 connected to the housing 123. Thehousing 123 can be a molded casing formed from a biocompatible materialthat has an interior cavity for carrying the pulse system 140. Thehousing 123 can alternatively be a biocompatible metal or anothersuitable material. The housing 123 can have a diameter of approximately1-4 cm, and in many applications the housing 123 can be 1.5-2.5 cm indiameter. The housing 123 can also have other shapes (e.g., rectilinear,oval, elliptical) and/or other surface dimensions. The signal deliverysystem 130 can weigh 35 g or less and/or occupy a volume of 20 cc orless. The attachment element 124 can be a flexible cover, a rigid plate,a contoured cap, or another suitable element for holding the supportmember 122 relative to the skull or other body part of the patient. Inone embodiment, the attachment element 124 is a mesh, such as abiocompatible polymeric mesh, metal mesh, or other suitable wovenmaterial. The attachment element 124 can alternatively be a flexiblesheet of Mylar®, a polyester, or another suitable material.

FIG. 9B illustrates a cross-sectional view of the signal delivery system130 after it has been implanted into a patient in accordance with anembodiment of the disclosure. In this particular embodiment, the system130 is implanted into the patient by forming an opening in the scalp 107and cutting a hole 108 through the skull 106 and through the dura mater109. The hole 108 should be sized to receive the housing 123 of thesupport member 122, and in most applications, the hole 108 should besmaller than the attachment element 124. A practitioner inserts thesupport member 123 into the hole 108 and then secures the attachmentelement 124 to the skull 106. The attachment element 124 can be securedto the skull using a plurality of fasteners 125 (e.g., screws, spikes,etc.) or an adhesive. In another embodiment, a plurality of downwardlydepending spikes can be formed integrally with the attachment element124 to define anchors that can be driven into the skull 106.

The embodiment of the system 130 shown in FIG. 9B is configured to beimplanted into a patient so that the electrodes 121 (e.g., electrodes121 a, 121 b) contact a desired portion of the brain at the stimulationsite. The housing 123 and the electrodes 121 can project from theattachment element 124 by a distance “D” such that the electrodes 121are positioned at least proximate to the pia mater 111 surrounding thecortex 110. The electrodes 121 can project from the housing 123 as shownin FIG. 9B, or the electrodes 121 can be flush with the interior surfaceof the housing 123. In the particular embodiment shown in FIG. 9B, thehousing 123 has a thickness “T” and the electrodes 121 project from thehousing 123 by a distance “C” so that the electrodes 121 apply a givenamount of pressure against the surface of the pia mater 111. Thethickness of the housing 123 can be approximately 0.5-4 cm, and is moregenerally about 1-2 cm. The configuration of the signal delivery system130 is not limited to the embodiment shown in FIGS. 9A-9B, but ratherthe housing 123, the attachment element 124, and the electrodes 121 canbe configured to position the electrodes 121 in several differentregions of the brain, and or in different manners. For example, inanother embodiment, the housing 123 and the electrodes 121 can beconfigured to position the electrodes beneath the cortical surface(e.g., at a selected location from just below the cortical surface todeep within the cortex 110), and/or a deep brain region 112. Suchtechniques can be used to provide signals to cortical target neuralpopulations within brain sulci and/or fissures, and/or beneath thecortical surface. In particular instances, stimulating deep brainstructures may facilitate plasticity in ASD patients.

The pulse system 140 shown in FIGS. 9A-9B generates and/or transmitselectrical pulses to the electrodes 121 to create an electrical field atthe target neural population. The particular embodiment of the pulsesystem 140 shown in FIG. 9B is an “integrated” unit in that it iscarried by the support member 122. The pulse system 140, for example,can be housed within the housing 123 so that the electrodes 121 can beconnected directly to the pulse system 140 without having leads outsideof the signal delivery device 120. The distance between the electrodes121 and the pulse system 140 can be less than 4 cm, and it is generally0.10 to 2.0 cm. The system 130 can accordingly provide electrical pulsesto the target neural population without having to surgically createtunnels running through the patient to connect the electrodes 121 to apulse generator implanted remotely from the signal delivery device 120.It will be appreciated, however, that in other embodiments, the pulsesystem 140 can be implanted separately from the signal delivery device120, within or outside the cranium.

FIG. 10 schematically illustrates details of an embodiment of the pulsesystem 140 described above. The pulse system 140 is generally containedin the housing 123, which can also carry a power supply 141, anintegrated controller 142, a pulse generator 143, and a pulsetransmitter 144. In certain embodiments, a portion of the housing 123may comprise a signal return electrode. The power supply 141 cancomprise a primary battery, such as a rechargeable battery, or othersuitable device for storing electrical energy (e.g., a capacitor orsupercapacitor). In other embodiments, the power supply 141 can be an RFtransducer or a magnetic transducer that receives broadcast energyemitted from an external power source and that converts the broadcastenergy into power for the electrical components of the pulse system 140.

In one embodiment, the integrated controller 142 can include aprocessor, a memory, and/or a programmable computer medium. Theintegrated controller 142, for example, can be a microcomputer, and theprogrammable computer medium can include software loaded into the memoryof the computer, and/or hardware that performs the requisite controlfunctions. In another embodiment identified by dashed lines in FIG. 10,the integrated controller 142 can include an integrated RF or magneticcontroller 145 that communicates with the external controller 146 via anRF or magnetic link. In such an embodiment, many of the functionsperformed by the integrated controller 142 may be resident on theexternal controller 146 and the integrated portion 145 of the integratedcontroller 142 may include a wireless communication system.

The integrated controller 142 is operatively coupled to, and providescontrol signals to, the pulse generator 143, which may include aplurality of channels that send appropriate electrical pulses to thepulse transmitter 144. The pulse transmitter 144 is coupled toelectrodes 1021 carried by a signal delivery device 1020. In oneembodiment, each of these electrodes 1021 is configured to be physicallyconnected to a separate lead, allowing each electrode 1021 tocommunicate with the pulse generator 143 via a dedicated channel.Accordingly, the pulse generator 143 may have multiple channels, with atleast one channel associated with each of the electrodes 1021. Suitablecomponents for the power supply 141, the integrated controller 142, theexternal controller 146, the pulse generator 143, and the pulsetransmitter 144 are known to persons skilled in the art of implantablemedical devices.

The pulse system 140 can be programmed and operated to adjust a widevariety of stimulation parameters, for example, which electrodes 1021are active and inactive, whether electrical stimulation is provided in aunipolar or bipolar manner, and/or how stimulation signals are varied.In particular embodiments, the pulse system 140 can be used to controlthe polarity, frequency, duty cycle, amplitude, and/or spatial and/ortopographical qualities of the stimulation. The stimulation can bevaried to match, approximate, or simulate naturally occurring burstpatterns (e.g., theta-burst and/or other types of burst stimulation),and/or the stimulation can be varied in a predetermined, pseudorandom,and/or other aperiodic manner at one or more times and/or locations. Thesignals can be delivered automatically, once initiated by apractitioner. The practitioner (and, optionally, the patient) canoverride the automated signal delivery to adjust, start, and/or stopsignal delivery on demand.

In particular embodiments, the pulse system 140 can receive informationfrom selected sources, with the information being provided to influencethe time and/or manner by which the signal delivery parameters arevaried. For example, the pulse system 140 can communicate with adatabase 170 that includes information corresponding to reference ortarget parameter values. The database 170 can be updated as the patientundergoes therapy, e.g., via the evaluation/adjunctive therapy system135 described above with reference to FIG. 1B. Sensors 160 can becoupled to the patient to provide measured or actual valuescorresponding to one or more parameters. The sensors 160 can be coupledto the patient's central nervous system (e.g., to the patient's motorcortex) to detect brain activity corresponding to incipient and/oractual hypertonicity behaviors. In particular embodiments, the sensors160 can include ECoG or EEG sensors. In another embodiment, the sensors160 can be peripheral sensors. In any of these embodiments, the measuredvalues of the parameter can be compared with the target value of thesame parameter (e.g., performance of a particular task), and the pulsesystem 140 can be activated if the measured value differs from thetarget value by more than a threshold amount. Accordingly, thisarrangement can be used in a closed-loop fashion to control whenstimulation is provided and when stimulation may cease. In oneembodiment, some electrodes 1021 may deliver electromagnetic signals tothe patient while others are used to sense the activity level of aneural population. In other embodiments, the same electrodes 1021 canalternate between sensing activity levels and delivering electricalsignals. In either of these particular embodiments, information receivedfrom the signal delivery device 1020 can be used to determine theeffectiveness of a given set of signal parameters and, based upon thisinformation, can be used to update the signal delivery parameters and/orhalt the delivery of the signals.

In other embodiments, other techniques can be used to providepatient-specific feedback. For example, a magnetic resonance chamber 165can provide information corresponding to the locations at which aparticular type of brain activity is occurring and/or the level offunctioning at these locations, and can be used to identify additionallocations and/or additional parameters in accordance with whichelectrical signals can be provided to further increase and/or facilitatefunctionality. Accordingly, the system can include a direction componentconfigured to direct a change in an electromagnetic signal applied tothe patient's brain based at least in part on an indication receivedfrom one or more sources. These sources can include a detectioncomponent (e.g., the signal delivery device and/or the magneticresonance chamber 165).

One aspect of the signal delivery device 1020 shown in FIG. 10 is thatit can include a support member 1022 that carries multiple electrodes1021 spaced apart along the generally linear axis. This arrangement canbe used to provide electrical signals to multiple target neuralpopulations, and/or to determine a particularly efficacious targetneural population by trial and error. FIG. 11 illustrates the signaldelivery device 1020 positioned over the left hemisphere 111 of thepatient's brain 110, so as to provide some electrodes 1021 over a firsttarget neural population 104 a (e.g., the superior temporal sulcusand/or other target site(s) associated with neural processing), andothers over the second neural target neural population 104 b (e.g., thesuperior temporal gyrus and/or other target site(s) associated withauditory processing). Accordingly, the same signal delivery device 1020can apply signals to multiple sites, with power to each of theelectrodes 1021 controlled individually so as to provide signals to theappropriate site at the appropriate time and in accordance with theappropriate signal delivery parameters. In an analogous manner, one ormore electrodes may be positioned proximate to target neural populationsat the patient's right hemisphere 112.

In other embodiments, the system can include signal delivery deviceshaving other configurations. For example, FIG. 12A is a top, partiallyhidden isometric view of a signal delivery device 1220, configured tocarry multiple cortical electrodes 1221 in accordance with anotherembodiment. The electrodes 1221 can be carried by a flexible supportmember 1222 to place each electrode 1221 in contact with a target neuralpopulation of the patient when the support member 1222 is implanted.Electrical signals can be transmitted to the electrodes 1222 via leadscarried in a communication link 1231. The communication link 1231 caninclude a cable 1232 that is connected to the pulse system 140 (FIG. 10)via a connector 1233, and is protected with a protective sleeve 1234.Coupling apertures or holes 1227 can facilitate temporary attachment ofthe signal delivery device 1220 to the dura mater at, or at leastproximate to, a target neural population. The electrodes 1221 can bebiased cathodally and/or anodally. In an embodiment shown in FIG. 12,the signal delivery device 1220 can include six electrodes 1221 arrangedin a 2×3 electrode array (i.e., two rows of three electrodes each, withrows spaced from each other by about 18 mm, and electrodes 1221 withinthe row spaced by about 9 mm), and in other embodiments, the signaldelivery device 1220 can include more or fewer electrodes 1221 arrangedin symmetrical or asymmetrical arrays. The particular arrangement of theelectrodes 121 can be selected based on the region of the patient'sbrain that is to be stimulated, and/or the patient's condition.

FIG. 12B is an internal block diagram of a system 1230 configured inaccordance with another embodiment of the invention. The system 1230 caninclude multiple pulse generators 1243 a, 1243 b and multiple outputs1247 a, 1247 b. Accordingly, the system 1230 may be coupled to two ormore signal delivery devices (e.g., two of the devices 1220 shown inFIG. 12A) to apply electromagnetic signals to different target neuralpopulations in one or more manners, which may depend upon the nature orextent of a patient's neurologic dysfunction and/or other embodimentdetails. The different target neural populations may reside in a varietyof anatomical locations, as discussed above. For example, a first and asecond target neural population may reside in the same or differentbrain hemispheres. A system having multiple pulse generators 1243 a,1243 b may stimulate different neural populations simultaneously orseparately, in an independent or correlated manner. One or both pulsegenerators 1243 a, 1243 b may generate stimulation signals in variousmanners described herein.

Other features of the system 1230 include a hermetically sealed housing1223 that houses a power source 1241 as well as a controller 1242, atelemetry and/or communication unit 1245, and a switching unit 1250.Depending upon embodiment details, the system 1230 may further compriseat least one programmable computer medium (PCM) 1248, which may becoupled to the controller 1242, the telemetry/communication unit 1245,the pulse generators 1243 a, 1243 b, and/or the switching unit 1250. Thesystem 1230 may additionally comprise at least one timing unit 1249.

The power source 1241 can include a charge storage device such as abattery. In some embodiments, the power source 1241 may additionally oralternatively comprise another type of device for storing charge orenergy, such as a capacitor. The controller 1242, the PCM 1248, thetelemetry/communication unit 1245, the pulse generators 1243 a, 1243 b,the switching unit 1250, and/or the timing unit 1249 may includeintegrated circuits and/or microelectronic devices that synergisticallyproduce and manage the generation, output, and/or delivery ofstimulation signals. In certain embodiments, one or more elements withinthe system 1230 (e.g., the communication unit 1245, the pulse generators1243 a, 1243 b, the switching unit 1250, and/or other elements) may beimplemented using an Application Specific Integrated Circuit (ASIC).

The timing unit 1249 may include a clock or oscillator and/or circuitryassociated therewith configured to generate or provide a set of timingreference signals to the controller 1242, the PCM 1248, thetelemetry/communication unit 1245, the pulse generators 1243 a, 1243 b,the switching unit 1250, and/or one or more portions, subelements, orsubcircuits of the system 1230. Such elements, subelements, and/orsubcircuits may correlate or synchronize one or more operations to oneor more timing reference signals, including the generation of othersignals in a manner understood by those skilled in the art.

The controller 1242 may control, manage, and/or direct the operation ofelements within the system 1230, e.g., on a continuous, near-continuous,periodic, or intermittent basis depending upon embodiment details. Thecontroller 1242 may include one or more portions of an integratedcircuit such as a processing unit or microprocessor, and may be coupledto the programmable computer medium (PCM) 1248. The PCM 1248 maycomprise one or more types of memory including volatile and/ornonvolatile memory, and/or one or more data or signal storage elementsor devices. The PCM 1248 may store an operating system, programinstructions, and/or data. The PCM 1248 may store treatment programinformation, system configuration information, and stimulation parameterinformation that specifies or indicates one or more manners ofgenerating and/or delivering stimulation signals in accordance withparticular embodiments of the invention.

The switching unit 1250 can include a switch matrix and/or a set ofsignal routing or switching elements that facilitate the application,delivery, and/or routing of stimulation signals to one or more sets ofelectrode assemblies, electrical contacts, and/or signal transferdevices at any given time. In one embodiment, the switching unit 1250may facilitate the electrical activation of particular electrodeassemblies, contacts, and/or signal transfer devices, possibly whileother such elements remain electrically inactive or electrically float.

Representative Diagnostic Procedures and Adjunctive Therapies

The following discussion provides additional details regardingprocedures for diagnosing ASD, and for supplementing the electromagneticsignal delivery treatment described above. In many instances, at leastsome aspects of the diagnostic procedure can also be used as part of anadjunctive therapy regimen, e.g., a behavioral therapy regimen that isperformed in conjunction with electromagnetic stimulation to enhanceneural connections and/or otherwise facilitate use of the patient'snatural neuroplasticity to address ASD.

In general, a representative procedure for treating ASD can take thefollowing form. First, using DSM IV and/or other assessments, a childwith pervasive developmental disorders (e.g., ASD), is evaluated to findspecific and prominent deficits that characterize the symptomology.Second, an assay is designed to determine the process or processesunderlying the deficit. The procedure generally includes a testassessment, data collection and theoretical analysis for each childindividually. The outcome determines, at least in part, the nature ofthe adjunctive therapy and the location(s) of the correspondingelectromagnetic signal delivery sites and associated signal deliveryparameters. Four representative implementations in social andcommunicative contexts are described below.

Example: Social Interaction

Diagnosis. In this example, a child is assessed as positive on thecharacteristics of DSM IV 1. The child exhibits qualitative impairmentin social interactions, as manifested by at least two of the following:marked impairment in the use of multiple nonverbal behaviors such aseye-to-eye gaze, facial expression, body postures, and gestures toregulate social interaction. A representative assessment is expected toidentify (e.g., pinpoint) the deficit as being associated with either orboth of two independent processes: hypo- or hypersensitivity of thenonverbal inputs corresponding to the nonverbal behaviors, and/or theinappropriate sensory integration of the inputs corresponding to thenonverbal behaviors.

Recognizing Emotion. An important feature of social interactions is forparticipants to be cognizant of the ongoing emotions of otherparticipants in the encounter. Important signals of emotion areavailable from two sources: the face (e.g., visual signals), and thevoice (e.g., auditory signals). Using these signals involves analyzingthe information in each signal and integrating (e.g., appropriatelycombining) the two signals to understand the emotion. Using the test andtheoretical paradigm described further below, the facial and vocalinformation presented to the patient is manipulated to determine (a) ifthe patient is sensitive to these independent signals and (b) if theyare integrated appropriately.

FIG. 13 illustrates a synthetic talking head, Baldig, programmed toexpress each of six emotional states during the articulation of a testword. The test word can be a semantically neutral stimulus word (e.g.,“please”) that is presented in any of the different simulated emotionalstates. In a particular embodiment, four of the six emotion categories(happy, angry, surprised, and fearful) are used to assess the patient.In this embodiment, the emotional expression presented by the face, andthe emotion conveyed by the articulation of the test word can be variedin a dependent manner to produce visually and auditorily consistentstimuli, or the facial expression and voice can be varied independentlyof each other to produce inconsistent stimuli. Further details regardingthe Baldie software are provided at www.animatedspeech.com andwww.mamboucsc.edu/psd/dwm.

Using an expanded factorial design shown in FIG. 14, the four emotions(happy, angry, surprised, and fearful) are presented auditorily,visually, and bimodally for a total of 24 combinations. For the eightunimodal presentations, either just the face or just the voice ispresented. For the sixteen bimodal presentations, the synthetic face ispresented along with the synthetic voice. Each audible word is presentedwith each visible word for a total of sixteen unique conditions. Twelveof the sixteen bimodal words have inconsistent auditory and visualinformation. In a particular embodiment, all of these conditions areused to achieve an informative picture of how these two modalities areprocessed.

Establishing a Standard. To implement this procedure with autisticindividuals, the practitioner will typically want to compare individualpatient data with data obtained from normal subjects. Accordingly, theparadigm can be carried out with normally developing individuals toobtain normative results at several age levels. To establish thestandard, normally developing children are instructed to watch thetalking head and listen to the voice during each trial. The children arethen asked to indicate which of the four emotion categories is beingcommunicated. The children can make their responses by entry into acomputer (e.g., via the input devices 102 shown in FIG. 1B) or by othersuitable methodologies. All of the test conditions can be randomized andpresented repeatedly for identification. The mean observed proportion ofidentifications can be computed for each of the 24 conditions for eachchild. Two groups of 24 students each can be tested to give a standardfor two age groups, e.g., five year olds and adolescents. In otherembodiments, standards for other age groups and/or more specific agegroups can be established.

FIG. 15 illustrates results from a hypothetical control group ofadolescents. Given that the participants' goal is to perceive theemotion, it is informative to evaluate performance in terms of accuracywith respect to each of the two modalities. The points in the left halfof FIG. 15 show average performance scored in terms of accuracy withrespect to the visible emotion. For unimodal trials, the average correctperformance, given just the face, is 0.94, 0.95, 0.73, and 0.64 for theemotion categories of happy, angry, surprised, and fearful,respectively. Thus, the average, normal subject is fairly good atidentifying the correct emotion from just the face, even when viewing asynthetic head.

The right half of FIG. 15 illustrates performance scored in terms ofaccuracy with respect to the auditory emotion. On the basis of unimodaltrials, correct identification given just the auditory informationaveraged 0.85, 0.60, 0.82, and 0.96 for the auditory emotion categoriesof happy, angry, surprised, and fearful, respectively. For the average,normal subject, happy, surprised, and fearful were relatively easy toidentify in the voice, whereas angry was somewhat more difficult.

There is evidence that recognizing auditory speech and facialinformation improves across development (see, for example, Massaro,1987, Chapter 8; and Massaro, D. W. (1998) “Perceiving talking faces:from speech perception to a behavioral principle”; Cambridge, Mass: MJTPress (hereinafter, “Massaro, 1998”) at 141-143). Therefore, it isexpected that data for average, normal 5 year olds will be about half asaccurate as for the adolescents shown in FIG. 15.

Patient Evaluation. Given the foregoing standard, autistic patients canbe tested and evaluated appropriately against the standard. The patientsare instructed to watch the talking head and listen to the voice duringeach trial, and to indicate which of the four emotion categories isbeing communicated. The patients can make their responses by inputs to acomputer (or via another suitable technique) using a patient-appropriateresponse method. Noninformative rewards or inducements can be presentedto keep each patient involved in the assessment. The test conditions canbe randomized and presented repeatedly for identification. The meanobserved proportion of identifications can be computed for each of the24 conditions for each patient.

The results for autistic patients can then be compared to results fornormal subjects. In a representative example, the average correctperformance of an autistic patient for unimodal trials, given just theface, may be 0.65, 0.55, 0.44, and 0.33 for the emotion categorieshappy, angry, surprised, and fearful, respectively. These performancevalues are significantly poorer than performance values for theadolescent standard group (0.94, 0.95, 0.73, and 0.64, respectively, asshown in FIG. 15). Thus, this patient reveals a significant deficit inrecognizing emotion from the face. Given this outcome, the practitionercan select an adjunctive treatment that includes a training programdirected to improving the patient's ability to recognize expressions offacial emotion. In addition, this information can be used by thepractitioner to bracket and/or pinpoint brain area(s) suitable forelectromagnetic stimulation.

A representative adjunctive treatment can include a behavioral therapyusing, for example, the Baldi® software described in this disclosure, ora therapist trained in techniques designed to develop the ability torecognize facial emotions. The adjunctive treatment can augmenttreatment via electrical and/or magnetic cortical stimulation. Thisstimulation can be targeted to specific cortical regions that normalsubjects use to process visual information received by viewing faces,including the right Fusiform Face Area which is located on the fusiformgyrus (FG, Brodmann area 36) on the ventral surface of the temporallobe. Existing studies have shown that this region is hypoactive in ASDpatients as compared to normal subjects. For example, FIGS. 16A-16F(adapted from Piercek et al; Brain (2001) 124:2059-2073, hereinafter“Piercek, 2001”), illustrate this effect. FIGS. 16A-16C illustrate Tmaps for autistic patients, with areas indicating statisticallysignificant de-activation identified by crosshatching on saggital,coronal, and axial cuts, respectively. FIGS. 16D-16F illustratecorresponding T maps for normal patients, with regions exhibitingstatistically significant de-activation indicated by crosshatching, andregions indicating statistically significant positive activationindicated by hatching. By comparing FIGS. 16A-16C with correspondingFIGS. 16D-16F, it is evident that autistic patients have hypoactiveneural populations at the FG, the right superior temporal sulcus (STS)and the left amygdala (Amy). Accordingly, the foregoing sites arerepresentative of sites a practitioner may select for electromagneticstimulation in a patient exhibiting deficits in the ability to recognizefacial emotions.

Results shown in FIG. 16A-16F are derived from group-averagedTalairach-normalized fMRI images. Unlike the normal subjects, ASDpatients do not exhibit a consistent location of significant activationin response to faces. Examination of individual-specific sites ofmaximal activation in ASD patients reveals a distinct region offunctional activation that can vary on a patient-by-patient basis, asshown in FIGS. 17A-17B (adapted from Piercek, 2001). FIG. 17Aillustrates a composite axial view of the brain, and FIG. 17Billustrates a composite saggital view of the brain. Each symbol shown inFIGS. 17A and 17B represents an activation “hot spot” for a singlesubject. For purposes of illustration, peak activations are showncollapsed across the superior-to-inferior axis on the axial image (FIG.17A) and across the left-to-right axis on the saggital image (FIG. 17B).Peak activations are shown with squares for autistic patients, and withcircles for normal patients. For every normal subject in this study, thesite of maximum activity was located in the FG. By contrast, each ASDpatient displayed a unique hot spot, only some of which were located inthe FG, while other were located in the frontal lobe, occipital lobe,and cerebellum. Variability in the location of maximal functionalactivation, and/or the level of activation in the FG, is expected toaccount for the behavioral deficit that ASD patients experience inreading emotions from faces, and is expected to contribute to theirsocial impairments. Behavioral training coupled with corticalstimulation in one or more of the regions shown to be involved inemotional face processing is expected to produce an increase infunctional activation in these regions, and lead to behavioralimprovements in ASD patients.

FIGS. 18A-18F (based on information presented in Piercek, 2001) furtherillustrate representative target neural populations in accordance withparticular embodiments. FIG. 18A is a ventral view of the brainillustrating the middle temporal gyrus (mTG), the inferior temporalgyrus (iTG) and the fusiform gyrus (FG). FIG. 18B is a coronal sectionof the brain, and FIG. 18C is a detailed portion of the coronal sectionshown in FIG. 1 8B, with the middle temporal gyrus, inferior temporalgyrus, and fusiform gyrus highlighted. FIG. 18D is a left lateral viewof the brain with the amygdala (Amy) highlighted. FIG. 18E is a coronalsection of the brain, also highlighting the amygdala, and FIG. 18F is adetailed view of a portion of the coronal section shown in FIG. 18E.

During a representative treatment regimen, the patient is instructed(e.g., via text presented at a computer display, such as the outputdevice 105 shown in FIG. 1B) to watch Baldi and indicate which emotionwas shown in the face. A 200 ms beep sounds prior to the presentation ofthe test stimulus to indicate the start of each trial. Following thetest presentation, response buttons appear in the upper left hand cornerof the display. The patient can respond by activating a correspondingsoft button labeled “happy,” “angry,” “surprised,” or “fearful” usingthe mouse, keypad, or touch screen. After the patient's response, theprocess can include providing feedback (e.g., via the display, or by thepractitioner) indicating the correct emotion that was presented. Theemotion stimulus is then repeated along with a description of theemotion. To keep the patient engaged, additional feedback can be givenfor correct responses in the form of “stickers” and verbal praise givenby Baldi. Training can continue at least until the child's performanceshows the normal skill in recognizing emotion in the face. Someovertraining may also be called for to achieve good retention.

A generally similar evaluation (and, when indicated, a correspondingtreatment regimen) can be carried out in the context of auditoryemotions. Returning to FIG. 15, a hypothetical standard for a normaladolescent subject is shown on the right side of FIG. 15. On the basisof unimodal trials, normal subjects presented with just the auditoryinformation (e.g., just a voice saying “please”) averaged 0.85, 0.60,0.82, and 0.96 for the auditory emotion categories happy, angry,surprised, and fearful, respectively. As indicated by these scores,happy, surprised, and fearful emotional states are relatively easy toidentify in the voice, whereas anger is somewhat more difficult. If anindividual patient performs significantly poorer than these standardvalues, the patient can receive a treatment that includes facial emotiontraining to train the patient to recognize emotions from speech. Inparticular, the training treatment can include a behavioral therapyusing, for example, the Baldi® software as described in this disclosure,or a therapist trained in techniques designed to develop the ability torecognize emotions from speech, in combination with electrical ormagnetic cortical stimulation. This stimulation can be targeted atspecific cortical regions including the superior temporal gyrus (STG),and especially the right STG, (Brodmann areas 22 and 42), as shown inFIGS. 19A and 19B, which are based on information presented by M.Zilbovicius et al. (2000) in Am. J. Psychiatry (157:1988-1993).

If the patient is reasonably capable of recognizing emotion in the faceand voice, the practitioner can assess the patient's multimodalintegration capabilities. FIG. 15 provides a representative standard fornormal adolescents performing multimodal integration tasks. Accuracydata are presented in FIG. 15 for bimodal trials, separately accordingto whether the two modalities are consistent or inconsistent with oneanother. Consistent modalities refer to multiple modalitiessimultaneously corresponding to the same emotion (e.g., both facialexpression and voice exhibiting a happy emotion) and inconsistentmodalities refer to multiple modalities simultaneously corresponding todifferent emotions (e.g., a happy facial expression coupled with anangry voice). When measured relative to the unimodal results, thebimodal results show a large influence of both modalities onperformance. Bimodal performance is expected to be close to perfect forall four emotion categories when the modalities are consistent. Thus,overall performance is more accurate with two sources of consistentinformation than with either source of information alone. Conversely,given inconsistent information from the two sources, performance ispoorer than observed in the unimodal conditions. The disruptive effectof inconsistent sources held strongly for all four emotion categories,with performance being poorer than observed when unimodal informationwas presented to the subject.

FIG. 20 illustrates the fraction of times each stimulus event wasidentified as a particular emotion, for each combination of visual andauditory stimuli. For example, the left-most box in the top row of FIG.20 indicates that when normal subjects are presented with a happy faceand a happy voice, nearly all the subjects identify the emotion ashappy. The next box to the right in the top row of FIG. 20 indicatesthat when normal subjects are presented with an angry face and a happyvoice, nearly all identify the emotion as anger, but some identify theemotion as happiness, and others as sadness. Although the results inFIGS. 15 and 20 demonstrate that both the face and the voice are used inemotion perception, they do not indicate that they were necessarilyintegrated. A formal theoretical analysis of these fine-grained resultscan accordingly be used to determine whether the facial and vocalemotions were integrated appropriately.

The analysis results shown in FIG. 20 provide a measure of whatalternatives are perceived given the different test conditions.Multimodal sensory integration predicts that perception will consist ofthe most reasonable alternative given the two inputs. This means thatthe two modalities are a better predictor of bimodal performance thanjust a single modality. The combination of surprise and fear provides anillustrative example. As can be seen in FIG. 20, when auditory surpriseis paired with visual fear, surprise is the dominant judgment. On theother hand, when auditory surprise is paired with visual anger, anger isthe dominant judgment. The difference between these two cases can beunderstood by the information available in the various inputs. In bothcases, the dominant response is that which agrees with the leastambiguous source of information. Auditory surprise is less ambiguousthan visual fear (see FIG. 15), hence when they are combined, surpriseis the dominant judgment. Auditory surprise is more ambiguous thanvisual anger (see FIG. 15), hence when they are combined, anger is thedominant judgment. These results are qualitatively consistent with theprinciple that the influence of one source of information when combinedwith another source is related to the relative ambiguity of the sourceswhen presented in isolation. The exact test of the influence of the twosources, and whether sensory integration occurs, involve model testing,which can be carried out on each patient. Additional details areprovided in Massaro, 1998.

Once the practitioner has assessed the patient's ability to recognizeemotion in the face and voice, the practitioner can assess the patient'sability to integrate the auditory and visual expressions of emotion. If,based on a comparison with the data shown in FIGS. 15 and 20, anindividual patient exhibits a deficit in multimodal sensory integration,the patient can receive a treatment program that emphasizes integratingsensory information from visual and auditory to recognize emotions fromfacial expressions and speech. The treatment can include a behavioraltherapy using, for example, the Baldi® software described above, or atherapist trained in techniques designed to develop the ability tointegrate visual and auditory inputs to recognize emotions, incombination with electrical and/or magnetic cortical stimulation. Thisstimulation can be targeted at specific cortical regions involved inprocessing faces and/or voices in normal subjects, including the rightsuperior temporal sulcus (Brodmann area 22), and/or the temporal pole(Brodmann area 38). These areas are expected to be responsible forsensory integration and are shown in FIGS. 21A and 21B. FIG. 21A is afrontal view of the brain, with the right side cut away to illustrateactivation peaks at the superior temporal sulcus. FIG. 21B illustrateslateral views of the brain for a control group and an autistic group,and illustrates active areas in the control group, which are generallyinactive for autistic patients. Information presented in FIGS. 21A-21Bis based on results presented by M. Zilbovicius et al. (2006) Rev. BrasPsiquiatr 28 (Supl 1): S21-S28.

The training session can follow the same general procedure as describedabove in the training to recognize emotion. However, therapy forenhanced multimodal integration may be somewhat more complex than thatassociated with unimodal training because patients are subjected to bothunimodal and bimodal stimuli. A representative type of therapy trialwill determine if the patient more accurately identifies consistent butsomewhat ambiguous emotions from the face and voice together than fromeither modality alone.

In a representative therapy regimen, the patient is instructed to watchBaldi's face, simultaneously listen to his voice, and indicate whichemotion was shown given both the face and the voice. In a particularembodiment, only consistent pairings will be presented—that is only asurprised voice will be paired with a surprised face, and so on for theremaining emotions. A 200 ms beep or other signal can be presented priorto presenting the test stimulus to indicate the start of each trial.Following the test stimulus, the patient can be presented (e.g., at acomputer screen) with response choices, and can respond by activating anappropriate button labeled “happy,” “angry,” “surprised,” or “fearful”using a mouse, touch screen or other input device. The system can thenprocess the response and provide an indication of the correct emotion.The emotion stimulus can be repeated along with a description of theemotion. To keep the patient engaged, additional feedback can be givenfor correct responses in the form of “stickers” and verbal praise givenby Baldi. Training can continue (in one or more sessions) at least untilthe patient's performance shows the normal skill in recognizing emotionin the face and voice. Some overtraining may also be provided to achieveenhanced retention.

Example: Communication

In this example, a child or other patient is assessed as positive on DSMIV 2: (qualitative impairments in communication) as manifested by adelay in, or total lack of, the development of spoken language, notaccompanied by an attempt to compensate through alternative modes ofcommunication, such as gesture or mime. A representative assessment(e.g., using the techniques described further below) can identify (e.g.,pinpoint) the deficit as associated with either or both of twoindependent processes: hypo- or hypersensitivity of speech inputs,and/or the inappropriate sensory integration of the speech inputs.

Speech perception refers generally to the process of imposing ameaningful perceptual experience on an otherwise meaningless speechinput (Massaro, 1998). There is now a large body of evidence indicatingthat multiple sources of information are available to support theperception, identification, and interpretation of spoken language(Massaro, 1998). Normal or typical language processing involves theevaluation and integration of these multiple sources of information. Anautistic child with qualitative impairments in communication can behypo- or hypersensitive to the inputs, and/or can fail to integrate thesources of information. The language assessment is illustrated below inthe context of face-to-face communication.

In normal subjects, speech perception is a bimodal process, influencedby both the sight and sound of the speaker (Massaro, 1998). Experimentshave shown that subjects of all ages are highly influenced by both theface and the voice when perceiving speech and understanding language(Massaro, 1998). Research has repeatedly shown that pairing somewhatnoisy auditory speech with visual speech from the face produces apercept that is more accurate and less ambiguous, compared to resultswhen presenting either of these modalities alone.

Children with autism might not show similar results for any of at leasttwo possible reasons. First, autistic children may have a problem withinitially processing the auditory and visual speech. They may havedifficulty perceiving and interpreting the subtle auditorycharacteristics that distinguish the unique segments in a givenlanguage. For example, the auditory difference between “b” and “d” is achange in frequency of the second formant at the onset of the sound. Forwhatever reason(s), autistic children may not resolve and use thisinformation as efficiently as normally developing children. In addition,children with autism are often known to have some difficulty readingfacial expressions (as discussed above) and therefore they may also havedifficulty lip reading the visible speech. The visual difference between“b” and “d” is that the mouth is closed at the onset of “b” but open atthe onset of “d”, and autistic children might have difficulty seeing andutilizing this distinguishing cue.

Second, independently of how well they process the separate auditory andvisual modalities, children with autism may have a deficit in performingsensory integration of the auditory and visual speech. For example, suchan integration process may be dependent upon mirror neurons and thesemight be dysfunctional in autism (see, e.g., Williams, J. H. G.,Massaro, D. W., Peel, N. J., Bosseler, A., & Suddendorf, T. (2004)“Visual-Auditory integration during speech imitation in autism”—Researchin Developmental Disabilities, 25, 559-575; and Williams, J. H., Whiten,A., Suddendorf, T., & Perrett, D. I. (2001) “Imitation, mirror neuronsand autism”—Neuroscience and Biobehavior Review, 25, 287-295). These twopotential deficits can be distinguished by examining speechreading(lipreading) ability on its own as well as in the context of the bimodalspeech perception task. A similar logic applies to the auditory speech,and the hypo- or hypersensitivity of the child to auditory speech can bedistinguished by examining the child's auditory speech perceptionability on its own as well as in the context of the bimodal speechperception task.

Because autistic communication dysfunction may result from either orboth of the foregoing deficits, assays in accordance with at least someembodiments distinguish between how much information is obtained from asensory input and how information is integrated from multiple inputs(Massaro, 1998). Within the framework for assessment, systems andmethods in accordance with particular embodiments can make a formaldistinction between “information” and “information integration.” Thesources of information from the auditory and visual channels first makecontact with the perceiver at a unimodal sensory evaluation stage ofprocessing. “Information” as used in this context can correspond to areduction in uncertainty provided by each source. For example, thedegree of support for each speech alternative from a given modalitycorresponds to information. Information integration, on the other hand,refers generally to integrating or combining the two sources ofinformation.

The foregoing analysis has been formalized in a prototypical patternrecognition model, the Fuzzy Logical Model of Perception (FLMP). Thismodel was developed to account for several important empiricalphenomena. The major assumptions upon which the FLMP is based are: 1)multiple sources of information influence speech perception, 2)perceivers have continuous information, not just categoricalinformation, about each source, and 3) the multiple sources are usedtogether in an optimal manner (Massaro, 1998). FIG. 22 illustrates theFLMP's three major operations in pattern recognition: evaluation,integration, and decision. The three perceptual processes are shown tooccur left to right in time to illustrate the successive but overlappingprocessing sequence. These processes make use of prototypes stored inlong-term memory. In this hypothetical situation given face-to-facedialog, the evaluation process transforms these sources of informationinto psychological values, which are then integrated to give an overalldegree of support for each speech alternative. The implicit decisionoperation maps the outputs of integration into some interpretation,which in behavioral experiments can take the form of a discrete decisionor a rating of the degree to which the alternative is likely.

As shown in FIG. 22, the sources of information are represented byuppercase letters. Auditory information is represented by A_(i) andvisual information by V_(j). The evaluation process transforms thesesources of information into psychological values (indicated by lowercaseletters a_(i) and v_(j)). These sources are then integrated to give anoverall degree of support, s_(k), for each speech alternative k, whichcould be as small as a speech segment or as large as an utteranceinterpretation. The decision operation maps the outputs of integrationinto some response alternative, R_(k). The response can take the form ofa discrete decision or a rating of the degree to which the alternativeis likely. The learning process is also included in FIG. 22. Feedback atthe learning stage is assumed to tune the psychological values of thesources of information used by the evaluation process.

Differences between the perceptual and learning processes are also shownschematically in FIG. 22. Perception is generally a feed-forward processin the sense that processing outcomes at a later stage do not feedbackand influence earlier stages. Similarly, top-down contextual effectsgenerally do not modify bottom-up perceptual processes. Feedback afterperception is assumed to tune the prototypical values of the featuresused by the evaluation process.

A representative assay, as implemented in accordance with the foregoingframework, allows the practitioner to distinguish information frominformation integration. A particular embodiment includes independentlymanipulating two sources of information in an expanded factorial design.It allows an assessment of the influence of the many potentiallyfunctional cues, and whether or how these cues are combined to achievespeech perception (see Massaro, 1998). This systematic variation of theproperties of the speech signal and quantitative analyses test howdifferent sensory sources of information are perceived and whether ornot they are integrated.

A representative assay uses a so-called expanded factorial designillustrated in FIG. 23. Stimuli can be presented by thecomputer-animated talking head, Baldi, described previously. Baldi'sspeech and emotion can be generated by a parametrically controlledpolygon topology (Massaro, 1998). An advantage of using thecomputer-animated talking head is that the stimuli presented by the headcan be precisely controlled and replicated over multiple trials. Baldican mimic natural speech, by incorporating coarticulation and being“trained” by natural speech measurements to accurately duplicate naturalspeech (Massaro, 1998; Massaro et al., “A multilingual embodiedconversational agent”—in R. H. Sprague (Ed.) Proceedings of 38th AnnualHawaii International Conference on Systems Science (HICCS), 2005). Thestimuli can include the consonant-vowel (CV) syllables “bi”, “vi”, and“di”. The synthetic visible speech is controlled and aligned with thesynthetic audible speech to produce a realistic simulation of a speakingperson.

As shown in FIG. 23, the synthetic auditory and visual stimuli arepresented unimodally and bimodally in an expanded factorial combination,giving a total of fifteen conditions. There are three auditoryconditions, three visual conditions and accordingly nine bimodalconditions. In a representative analysis, each of the fifteen totalconditions is sampled randomly without replacement in a block of trials.

The set of fifteen stimuli can be repeated a number of times for eachpatient. The results can be analyzed to determine how the sensorysources of information are perceived and whether or not they areintegrated. This outcome can then be used to determine, at least inpart, a rehabilitative therapy regimen. For example, in some cases, thepractitioner may determine that the patient is capable of perceivingauditory speech but is not able to lipread, and accordingly fails toobtain the benefit of visual cues in face-to-face communications. Insuch cases, the patient can be trained to lipread syllables whilecortical stimulation is applied to the appropriate brain area.

As discussed previously, much of the visual processing of facialexpression in normal subjects is located in the fusiform face area (FFA)located on the fusiform gyrus (FG). In addition, language processing ispredominantly carried out in the left hemisphere in normal subjects.Thus, the practitioner can select the left FFA as a cortical target areafor facilitating lip reading in ASD patients.

During a treatment regimen in accordance with a particular embodiment,the patient is instructed to watch Baldi and indicate the syllable thatwas spoken. A 200 ms beep or other suitable signal is presented prior tothe presentation of the test stimulus to indicate the start of eachtrial. Following the test presentation, response buttons or othersuitable input devices are presented to the patient, e.g., in the upperleft hand corner of a computer-driven display. The patient responds byselecting “B,” “V,” or “D,” using a mouse, touch screen or appropriatelylabeled button. To keep the patient engaged, feedback can be given forcorrect responses in the form of “stickers” and verbal praise given byBaldi. Treatment including the foregoing adjunctive behavior incombination with cortical stimulation can continue until the patient'sperformance shows the normal skill in lipreading.

Once the patient's lipreading ability is established and/or improved,the practitioner can repeat the original assay to evaluate the abilityof the patient to integrate the auditory and visual components ofspeech. If a deficit in sensory integration is identified during theassay, the practitioner can initiate a therapy regimen that includes oneor more corrective treatments that emphasize sensory integration, incombination with cortical stimulation. The behavioral therapy can followthe same general procedure as described previously in the content of themultimodal sensory integration training.

The target neural population stimulated to facilitate sensoryintegration for enhanced communication can include the left superiortemporal sulcus (Brodmann area 22), and in particular embodiments,Wernicke's area located on the more posterior aspect of the STS. Twoother adjoining areas, the angular gyrus (Brodmann area 39) andsupramarginal gyrus (Brodmann area 40), are also typically involved withsensory integration of speech. Accordingly, stimulating these areas mayalso facilitate sensory integration development in specific ASDpatients,.

Example: Use of Contextual Information in Speech Perception

One of the landmark abilities of humans is to benefit from thesituational context of social and communication encounters. Our oftenseamless ability to understand language, for example, is highlydependent on knowing the language being spoken. A common impression isthat foreign languages are spoken very rapidly without pauses. In fact,all languages are spoken at roughly the same rate with very few pausesbetween successive words. We tend to “hear” pauses because of ourknowledge of the words.

One important measure of autistic behavior is the extent to which thepatient uses context. A representative diagnostic/therapeutic regimenincludes assaying the patient's ability to use context in one or more ofseveral ways, and then developing therapies that include teaching theuse of context, in combination with stimulating the appropriate brainarea. One test includes measuring lexical influences in speechperception by manipulating the segmental information in a speech itemand the lexical context. The initial speech segment will be synthesizedto vary the degree to which it sounds like “d” or “t.” The voice onsettime or the time between the initial burst of the sound and the onset ofvocal cord vibration will be varied in small steps to produce a set oftest stimuli between “d” and “t.” This speech segment will be placed asthe initial consonant before the contexts “urf” and “irt.” The consonant“t” makes a word in the context urf whereas “d” makes a word in thecontext “irt.” During the test, these sound combinations are randomlypresented to listeners who are asked to indicate whether the initialsegment was a “d” or “t.” The judgments of normally functioninglisteners are influenced by both the initial speech segment and thecontext. The results indicate that the likelihood of a “t” judgmentincreases as the voice onset time is lengthened. In addition, “t”judgments are more frequent in the context “urf” than “irt,” inagreement with an influence of lexical context. The influence of lexicalcontext is greatest at the more ambiguous levels of initial segment, aspredicted by an integration model (Massaro, 1998).

Using the foregoing technique, a practitioner can assess whether and towhat extent a patient uses the initial segment information and thecontext information, and whether and to what extent these two sourcesare integrated. The outcome of the assessment can determine, at least inpart, an appropriate therapy, analogous to those described previously inthe contexts of social interaction and communication.

In particular embodiments, the cortical target stimulated to facilitatethe use of contextual information in speech perception is the leftsuperior temporal gyrus (Brodmann area 42) and in other embodiments,other areas may be stimulated, e.g., if such areas are determined toplay a role in the patient's use of contextual information.

Example: Influence of Context on Comprehension

Many children with autism do acquire language and learn to read but theycontinue to have difficulty taking into account context. In reading, forexample, their pronunciation and therefore interpretation of homographsis not appropriately constrained by context. (Snowing, M. & Frith, U.(1986) “Comprehension in “hyperlexic” readers,” Journal of ExperimentalChild Psychology, 42, 392-415). For example, consider the sentences: “Ilive just across the lake” and “I saw a live animal in the backyard.”Typically developing readers will pronounce these two versions of “live”differently and appropriately in the two contexts. Autistic patients canbe assessed in a test that evaluates how homographs such as “live,”“bow,” and “lead” are read in context. If a patient shows insensitivityto context in his or her reading, a treatment regimen can be related toteach these contextual constraints while the appropriate brain area isstimulated. For example, in one type of training session, the patientwill see a written text simultaneously with an aural reading of thetext. As the text is read, the written word that is being spoken will behighlighted, so the patient can follow along silently reading the textas it is being spoken. In this way, the patient can be trained toassociate the appropriate reading of a word, given the constrainingcontext. In addition to these training trials, the patient can be testedby reading aloud the same texts and new texts. The cortical targetstimulated to facilitate the influence of context on comprehension caninclude the left superior temporal gyrus (Brodmann area 22) and/or othersuitable areas.

Example: Early Visual and Auditory Integration

The tasks described to this point have involved fairly sophisticatedprocessing such as recognizing emotion, speech, words, or languagecomprehension. In some cases, patients may have deficits in the earlystages of multisensory processing. In a well-known illusion, sound caninduce a visual flash illusion (Shams, L, Kamitani Y, Shimojo, S (2000)“What you see is what you hear,” Nature, 408, 788). If a short flash ispresented, people correctly report a single flash. If the same flash ispresented with two short sounds, the single flash is perceived as two.This task can be used to assess to what extent an autistic patient hasdeficits in integration of auditory and visual information. Autisticchildren can be tested in this task to see if they experience theillusion. If they do not, then an appropriate training regimen can beinitiated with stimulation of the appropriate brain area. The corticaltargets stimulated to facilitate early visual and auditory Integrationcan include Brodmann areas 37 and 39.

Example: Early Visual and Tactile Integration

A task similar to that described above includes interactions betweenvisual information with somatosensory information (Violentyev A, ShimojoS, Shams L. (2005) “Touch-induced visual illusion,” Neuroreport, Vol.16. No. 10 (13 Jul. 2005), pp. 1107-1110). For example, people havereported seeing two flashes when a single flash is paired concurrentlywith two brief tactile stimuli. An assay and treatment regimen generallysimilar to that described above (with tactile stimulation substitutedfor auditory stimulation) can accordingly be administered to thepatient. The cortical target stimulated to facilitate early visual andtactile integration can include Brodmann area 7.

Although the proposed tests and training regimens have been described inthe domain of autism, they are equally applicable to similar symptoms inother disabilities like dyslexia, speech language impairment, ADHD, andlearning delays/disabilities.

From the foregoing, it will be appreciated that specific embodiments ofthe disclosure have been described herein for purposes of illustration,but that various modifications may be made without deviating from thedisclosure. For example, many of the foregoing tests and trainingregimens were described in the context of autism. In other embodiments,identical and/or generally similar tests and training regimens may beapplicable to patients having similar symptoms, but other disabilities.Such disabilities can include dyslexia, speech language impairment,ADHD, and/or learning delays/disabilities. As was also discussed above,many of the stimulation techniques include stimulation via electrodesplaced at or above the cortical surface of the brain, but in otherembodiments, suitable stimulation may be applied by electrodespositioned beneath the cortical surface (e.g., penetrating electrodes)and/or by signal delivery devices placed outside the patient skull(e.g., transcranial magnetic stimulation devices or transcranial directcurrent stimulation devices). The “stimulation” signals can haveinhibitory affects, excitatory affects, and/or affects that enhanceneuroplasticity.

Certain aspects of the disclosure described in the context of particularembodiments may be combined or eliminated in other embodiments. Forexample, techniques and/or devices described in the context ofaddressing particular patient symptoms may be adjusted to address othersymptoms. In a particular example, the electrodes shown in FIG. 11 maybe placed at other locations of the brain to address other patientdysfunctions. In general, it is expected that the foregoing techniquescan more accurately identify target neural populations, and thus providemore effective treatment. While advantages associated with certainembodiments of the disclosure have been described in the context ofthose embodiments, other embodiments may also exhibit such advantages,and not all embodiments need necessarily exhibit such advantages to fallwithin the scope of the disclosure. Accordingly, aspects of theinvention may cover embodiments not expressly shown or described herein.

1. A method for treating a patient dysfunction, comprising: determiningthat the patient suffers from an autism spectrum disorder; based atleast in part on the determination that the patient suffers from anautism spectrum disorder, selecting a cortical signal delivery site;implanting an electrode within the patient's skull and external to acortical surface of the patient's brain; and treating the autismspectrum disorder by applying electrical signals to the implantedelectrode in conjunction with administering an adjunctive therapy to thepatient.
 2. The method of claim 1 wherein selecting a cortical signaldelivery site includes selecting a hypoactive target neural location. 3.The method of claim 2 wherein selecting a cortical signal delivery siteincludes selecting Brodmann area
 36. 4. The method of claim 1 whereinselecting a cortical signal delivery site includes selecting apatient-specific signal delivery site.
 5. A method for treating apatient dysfunction, comprising: determining that a patient suffers froman autism spectrum disorder; evaluating the individual patient'sresponses to first auditory and visual stimuli corresponding to humanemotional states; based at least in part on the individual patient'sresponses, determining whether the patient has a neurological defectassociated with responding to auditory stimuli, visual stimuli or both;based at least in part on the determination of the patient'sneurological defect, selecting a cortical signal delivery site that isdifferent depending on whether the defect is associated with respondingto auditory stimuli, visual stimuli or both; implanting an electrodewithin the patient's skull and external to a cortical surface of thepatient's brain; and treating the autism spectrum disorder by applyingelectrical signals to the implanted electrode in conjunction withadministering an adjunctive therapy to the patient, wherein theadjunctive therapy includes presenting the second auditory and visualstimuli corresponding to human emotional states.
 6. The method of claim5 wherein presenting first auditory and visual stimuli includespresenting auditory and visual stimuli separately.
 7. The method ofclaim 5 wherein presenting first auditory and visual stimuli includespresenting auditory and visual stimuli together.
 8. The method of claim7 wherein presenting first auditory and visual stimuli together includespresenting an auditory stimulus that is inconsistent with a visualstimulus, and wherein determining whether the patient has a neurologicaldefect includes determining whether the patient has a defective abilityto integrate auditory and visual stimuli.
 9. The method of claim 5wherein presenting second auditory and visual stimuli includespresenting second auditory and visual stimuli that are generallyidentical to the first auditory and visual stimuli.
 10. The method ofclaim 5 wherein presenting the first auditory and visual stimuli, thesecond auditory and visual stimuli, or both the first and secondauditory and visual stimuli includes presenting the stimuli via acomputer-based synthetic depiction of a human face.
 11. A method fortreating a patient dysfunction, comprising: determining that the patientsuffers from an autism spectrum disorder; based at least in part on thedetermination that the patient suffers from an autism spectrum disorder,selecting a target neural population of the patient's brain; andtreating the autism spectrum disorder by delivering electromagneticsignals to the target neural population.
 12. The method of claim 11,further comprising identifying the target neural population as beinghypoactive, and wherein delivering electromagnetic signals includesincreasing the activation level of the target neural population.
 13. Themethod of claim 12 wherein delivering electromagnetic signals includesdelivering electromagnetic signals at a frequency greater than about 5Hz.
 14. The method of claim 11, further comprising identifying thetarget neural population as being hyperactive, and wherein deliveringelectromagnetic signals includes decreasing the activation level of thetarget neural population.
 15. The method of claim 14 wherein deliveringelectromagnetic signals includes delivering electromagnetic signals at afrequency of less than 5 Hz.
 16. The method of claim 11, furthercomprising promoting cortical organization of the patient's brain byadministering a behavioral adjunctive therapy in conjunction withdelivering electromagnetic signals.
 17. The method of claim 16 whereinadministering a behavioral adjunctive therapy includes administering atraining program to the patient to train the patient to recognizeexpressions of facial emotion.
 18. The method of claim 16 whereinselecting a target neural population includes selecting the targetneural population to include at least one of the amygdala, the superiortemporal sulcus, and Brodmann area
 36. 19. The method of claim 11wherein delivering electromagnetic signals includes deliveringelectromagnetic signals from an implanted electrode positioned beneaththe patient's skull and external to a cortical surface of the patient'sbrain.
 20. The method of claim 11 wherein delivering electromagneticsignals includes delivering electromagnetic signals from a site externalto the patient's skull.
 21. The method of claim 20 wherein determiningthat the patient suffers from an autism spectrum disorder includesdetermining that a child patient suffers from an autism spectrumdisorder, and wherein delivering electromagnetic signals includesdelivering electromagnetic signals via transcranial magneticstimulation.
 22. The method of claim 11 wherein deliveringelectromagnetic signals includes delivering electromagnetic signals froman implanted electrode positioned beneath a cortical surface of thepatient's brain.
 23. A patient diagnostic/treatment system, comprising:a test component programmed with instructions to provide visual and/orauditory stimuli to a patient and receive patient responses; anevaluation component programmed with instructions to identify a targetneural population based at least in part on information received fromthe test component; and a signal delivery device configured to applyelectromagnetic signals to the target neural population.
 24. The systemof claim 23, further comprising an adjunctive therapy componentprogrammed with instructions to provide visual and/or auditory stimulito the patient in conjunction with the delivery of electromagneticsignals.
 25. The system of claim 23 wherein the signal delivery deviceincludes an implantable electrode and pulse generator.
 26. The system ofclaim 23 wherein the signal delivery device includes a transcranialmagnetic stimulator.
 27. The system of claim 23 wherein the testcomponent is programmed with instructions for providing consistentvisual and auditory stimuli via a computer-based simulation of a humanface.
 28. The system of claim 23 wherein the test component isprogrammed with instructions for providing inconsistent visual andauditory stimuli via a computer-based simulation of a human face. 29.The system of claim 23 wherein the evaluation component is programmedwith instructions for comparing the patient responses with data fornormal patients.
 30. The system of claim 23 wherein the evaluationcomponent is programmed with instructions that discriminate betweenpatient responses indicating a defect in processing unimodalinformation, and patient responses indicating a defect in integratingmultimodal information.